Pancreatic cancer is the fourth leading cause of cancer-related mortality in the United States, and 95% of patients who develop pancreatic cancer die from their disease. Unfortunately, relatively little is known about the pathogenesis and epidemiology of this under-studied malignancy. To address this problem, the current proposal focuses on the investigation of dietary, genetic and biochemical risk factors for pancreatic cancer. For Aim 1, I will examine a novel dietary index that estimates long-term systemic insulin exposure and two hormones altered in states of obesity and insulin resistance, adiponectin and leptin. For Aim 2, I will investigate plasma markers of inflammation, Helicobacter pylori infection, and telomere length, in an effort to better understand the link between chronic inflammation and, pancreatic cancer risk. For Aim 3, I will expand on recent observations linking heterogeneity at the ABO blood group locus with plasma inflammatory markers and the risk of pancreatic cancer. A major strength of this proposal is the ability to examine these factors prospectively, thereby avoiding the problems associated with retrospective analyses of pancreatic cancer epidemiology. Moreover, this proposal will assemble one of the largest prospective case-control sets to date, establishing a unique database of pancreatic cancer cases and matched controls, with repeated dietary and lifestyle assessments over several decades, archived blood specimens, and genomic DNA. This resource will allow me to rigorously examine multiple inter-related pathways with robust power. In addition, it will allow me to rapidly examine new hypotheses as they emerge. Finally, this award will enable me to develop advanced skills in biostatistics and epidemiology, pursue a focused program in pancreatic cancer research, and receive close, long-term mentorship from experienced and successful clinical researchers, promoting my transition to an independent investigator. RELEVANCE: Although pancreatic cancer is the 4th most common cause of cancer-related death in the U.S., we know little about predisposing factors for this disease. With the current proposal, I hope to advance our understanding of pancreatic cancer pathogenesis, generate an important resource to evaluate future hypotheses, and provide data to support recommendations for reducing mortality from this highly lethal malignancy.